Friedrich boedecker



Patented Mar. 22,- 1927.

' UNITED STATES PATENT OFFICE.

' FRIEDRICH nonnncxna, or BERLIN-Bantam, GnnMAnY, ASSIGNORY To run 1mm I. 1). runner. A. 0., or IBERLIN-IBRITZ, GERMANY.

BARBI'I'URIC ACID AND PROCESS OF MAKING SAME.

No Drawing. Application filed September 28, 1924, Serial No. 789,426, and in Germany October 10, 1928.

I have now found that barbituric acid compoundshaving a substituted methylene group in which at least one of the hydrogen atoms of the methylene group is substituted 5 by a halogenallyl. group containing a halogen at least in the ,B-position, possess quite extraordinary hypnotic power and are more effective than the barbituric acids hitherto employed for this purpose. The second hydrogen atom of the methylene, can also be substituted by a halogenallyl e.' g. B- or y-bromallyl radical or by any other alkyl, (for instance isopropyl or diethylmethyl group) aryl, or alicyclic radical.

The production ofthenew compound can be carried out by preparing amalonic acid ester of the general formula a cooa R'/ cooR in which ,R" is a halogenallyl especially fi-bromallyl, or fi- -dibromallyl, R a hydrogen atom, a halogenallyl e. g. B- or -bromallyl or any aliphatic, aromatic or alicyclic radical, for example'by acting on the sodium compounds of malonic acids, their chlorides, esters or derivatives, for example the cyanacetic ester or its already mono substituted derivatives, with 1.2-dibrom- 0 2.3-propylene, and these compounds are then transformed into the corresponding barbituric acids in the usual manner. It will be understood that the usual manner here referred to, may consist in causing a malonic acid compound to react with ureaor a'derivative thereof, analogously to the formation of the barbituric acid NH-OO to Instead of starting with urea one may also use substituted ureas, guanidine, thiourea, etc, as startlng materials.

I have also found that ii: 1s not necessary and permitting this to act on barbituric acids in the presence of alkali. The splitting off of hydrohalogenic acid occurs so easily that the reaction can-even be carried out at ordinary temperature. The splitting oflI' of hydrohalogenic acid. also can naturally be carried out first and then the condensation brought about. In both cases one can obtain the B-halogenallyl acids directly from 1.2.3-trihalogenpropane which facilitates the production of the valuable products characterized by their extraordinary hypnotic powers. By application of trihalogenpropylene I obtain the corresponding ,B y-halogenallyl compounds.

Example 1.

' 170 parts of isopropyl'barbituric acid are gradually added (e. g. at room temperature) 1 to a sodium ethylate solution preparedfrom 23 parts of sodium and warming (say at 85 C.) with brisk agitation, and finally 240 parts of 1.2-dibrom2-.3-propylene are permitted to flow in slowly. After heating for several hours at -100 the reaction is completed. After blowing ofi the alcohol the B brom'allyl-isopropylbarbituric acid is recovered in almost quantitative yield in the form of colorless crystals.

After recrystallization from dilute acetic I acid the acid shows a melting point of 181. Formula of reaction:

i Example 2. p 250 parts of dibrompropylene are added to a clear solution of 170 parts of isopropylbarbituric acid in dilute caustic soda solu-- isopropylbarbituric acid is filtered by suction'and recrystallized from water or dilute acetic acid.

Any untransformed isopropylbarbituric acid is recovered from the filtrate after separatingout the unchanged dibrompropylene, by precipitation with concentrated hydrochloric acid.

Formula of reaction:

Ewample 128 parts by Weight of barbiturie acid is dissolved in 2000 parts (by volume) caustic soda solution containing parts by weight of caustic soda, and. while warming, several hours stirred well with 440 parts by weight of dibron'ipropylcne. After the dibrompropylenc has disappeared the reaction is regarded as finished. Upon cooling, the product of reaction is separated out and liltered by suction. After recrystallization from alcohol in the presence of animal charcoal the di-B-brom allyl barbituric acid is recovered in the form of colorless crystals, showing a melting point of 232-233. 'It is soluble in alcohol. acetone and alkalies, little soluble in ether, benzol. water.

Formula of reaction:

170 parts by weight of isopropylbarbituric acid is dissolved in a solution of 80 parts by weight ol caustic soda in 600 parts o't' water, 280 parts by weight of lribronipropane added and the whole dissolved to a homogeneous mixture by the addition of 2000 parts by volume of ordinary alcohol. The reaction mixture is heated for several hours on the steam bath and the alcohol then removed with steam. Toward the end of the. distillation iso iropyl-bromallyl-barhituric acid separates in the form of crystals in the flask. The yield is 195 parts.

By r'ecrystallization from dilute alcohol the acid ffrecovered in a pure state having a melting point e t 4181".

co+cmm-ciim-ciuur-izmou 11 coxn (Cum on CONII s. CO+2Nalr+2lh0 cm our-cm GONll Example 5.

280 parts by weight of trihrompropane are heated for an hour at 80 C. umlcr a reflux condenser with 40 parts by weight of caustic soda in small pieces the size of peas. After cooling. :1 solution of parts by weight of phcnylbarbituric acid in caustic soda solution of 7% containing 40 parts by weight sodium hydroxide is added and mixed with 1800 parts by volume of alcohol until the mixture becomes homogeneous. After warming for several hours at the temperature of a water bath the reaction is complete. The alcohol is distilled off under diminished pressure and phenvl-bromallylbarbituric acid separates out in the flask. Yield 225 parts.

After recrystallization from dilute acetic acid the acid shows a melting point of 199-1809 It is easily soluble in alcohol. glacial acetic acid. alkalics and soda solution.

The splitting oil of livdrohromic acid from triln-omhydrine can naturally also be carried out by means of alcoholic alkali.

Formula of reaction:

Emma-pie 6.

170 parts by Weight isopropylbarbituric acid is dissolved in 500 parts (by volume) double normal caustic soda. solution. After adding 125 parts (by weight) dichlorpropylone the mixture is heated several hours under a reflux condenser. The precipitated product of reaction is filtered off by suction and recrystallized from dilute alcohol. The B- chlorallylisopropylbarbituric acid thus obtained appears in the form of long colorless needles. melting at 171. The acid is soluble in alcohol, other, acetone. little soluble in chloroform. tcra hydrogenated naphthalene and water. From sodium carbonate solution or caustic soda solutions the acid is separated unchanged by addition of acids. The same acid is obtained by reaction in the same manner of" .2-chlor-S-brompropylene-l with the sodium salt of the isopropylbarbituric acid (formula of: reaction analogous to EX- ample 4).

Ermmple 7.

170 parts by weight of isopropylbarbituric acid are dissolved lll caustic soda solutlon of 7% containing 40 parts by weight caustic soda. After adding a small quantity otassium iodide and 290 parts by Weig t of 1.2.3-triln'ompropylene the mixture is heated while vigorously stirring. After some working the separated crystalline product is'filtered oil by suction and, when necessary, washed with gasoline. By recrystallization from methyl alcohol the B-y-dibromallylisopropylbarbituric acid is obtained in pure state with melting point of 182-183 and soluble in ethylalcohol, chloroform, ether, benzol. -caustic soda solution, sodium carbonate iolution. little soluble in gasoline, cy-

clohexane. niethylcyclohexane, water.

Formula of reaction: (CH:):=CH\C CONH H/ CONH onm=cn CONH CHBrzCBr-CH/ CONH I claim: 1. As new products, the herein described substituted barbituric acids in which at least one of the hydrogen atoms of the methylene group is substituted by a halogenallyl group containing halogen at least in the ,B-position.

2. As new products the herein described barbituric acid in whiclrat least one of the hydrogen atoms of the methylene group is replaced by B-halogenallyl.

3. As new products, the herein described Substituted barbituric acids in which at least one of the hydrogen atoms of the methylene group is replaced by fl-bromallyl.

4. As new products, the herein described substituted barbituric acids in which at least one of the hydro en atoms of the methylene group is replaced by dihalogenallyl.

5. As new products, the herein described substituted barbituricacids in which at least one of the hydrogen atoms of the methylene group is replaced by a halogenated allyl group.

6. Process of preparing hypnotic derivatives of barbituric acids, which comprises substituting at least one of the hydrogen atoms of the methylene group of the barbituric acids by halogenallyl, containing halogen at least in the ,8-position.

7. A method of forming substituted barbituric acids, which comprises treating barvbituric acid, in which at least one of the hydrogen atoms of the methylene group is free, with halogen prop lene in presence of alkali.

8. A'meihod of forming substituted barbiturieacids, which comprises treating barbituric acid, in which at least one of the hydrogen atoms of the methylene group is free, with 1.2.3-trihalogenpropane in presence of alkali.

In testimony whereof I aflix my signature.

DR. FRIEDRICH- BOEDEGKER. 

